Avibactam sodium belongs to the class of non-beta-lactam beta-lactamase inhibitors and is intended to be used in conjunction with beta-lactam antibiotics for the treatment of bacterial infections. It protects beta-lactam antibiotics from degradation by beta lactamase enzymes and therefore maintains the antibacterial activity of beta-lactam antibiotics.
WO 02/10172 A1 describes the racemic sodium salt of trans-7-oxo-6-sulfooxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide in crystalline form and a method for its preparation.
However, it was found that only one enantiomer is active, which is the sodium salt of (1R,2S,5R)-7-oxo-6-sulfooxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (international non-proprietary name: avibactam sodium) represented by chemical structure (I)

WO 2011/042560 A1 describes avibactam sodium crystalline forms A, B, D and E and mentions a mixture of at least one of these forms with a form C. It does however not contain any disclosure for the preparation of a form C or said mixtures.
WO 2014/135930 A1 discloses a crystalline form of avibactam sodium characterized by powder X-ray diffraction. According to the peak list provided on page 6 and the corresponding powder X-ray diffractogram of FIG. 1 this crystalline form can be assigned to a mixture of crystalline forms of avibactam sodium comprising at least form B and form D of WO 2011/042560 A1, while form C is not present.
It is well-known by the skilled person that upon temperature stress or under acidic or basic conditions hydrated forms often tend to hydrolyze. Hydrates are also prone to dehydration, for example, they readily lose their water when subjected to dry conditions and/or increased temperatures. For example, WO 2011/042560 A1 mentions that the avibactam sodium dihydrate form E tends to lose water and to hydrolyze during long storage and at higher temperature (page 17, lines 1 to 2). It is further stated in the application that form E is particularly stable above relative humidities of about 70% (page 15, line 25), indicating that this hydrated form is only stable in the presence of moisture. In addition, it was found that form E dehydrates to the monohydrate form A at temperatures above about 60° C. and that form A upon further temperature stress dehydrates to the anhydrous form B. Such conversions of physical forms are critical as pharmaceutical processing and milling usually involves the evolution of heat. Hence, for pharmaceutical purposes anhydrous forms of avibactam sodium are preferred over hydrates.
Besides proper physical properties, the manufacturability of a solid form determines whether it is a feasible candidate for the preparation of a drug product. According to WO 2011/042560 A1 (page 16, lines 30 to 31) anhydrous form D was only obtained as very small crystals, making filtration difficult and slow and hence making it difficult to prepare form D. Thus, due to its limitations with regard to isolation, form D cannot be produced on an industrial scale. In addition, the robustness and reliability of a manufacturing process is a key criterion for physical form selection. WO 2011/042560 A1 (page 17, lines 8 to 14) for example mentions that anhydrous form B is difficult to prepare in the absence of seed crystals and only obtained in a very narrow range of water activity. The seed crystal preparation disclosed in the application (page 16, lines 22 to 26) seems not to be straightforward, let alone industrially applicable. Therefore, a reliable industrial production of anhydrous form B seems to be very challenging.
An objective of the present invention was therefore the provision of a crystalline form, preferably a crystalline anhydrous form of avibactam sodium which is polymorphically stable, i.e. which does not convert to any other physical form of avibactam sodium during pharmaceutical processing and/or upon storage. A further objective was the provision of avibactam sodium in a crystalline form, preferably in a crystalline anhydrous form which is polymorphically pure or essentially polymorphically pure, i.e. is free or essentially free of any other physical form of avibactam sodium. Further, it is an objective to provide a solid pharmaceutical composition comprising a crystalline form, preferably a crystalline anhydrous form of avibactam sodium, wherein the crystalline (anhydrous) form of avibactam sodium is polymorphically stable within the pharmaceutical composition and under various conditions, e.g. at ambient storage conditions. In addition, it is an objective to provide a solid pharmaceutical composition comprising a crystalline form, preferably a crystalline anhydrous form of avibactam sodium, wherein the crystalline (anhydrous) form of avibactam sodium is present in polymorphically pure form or essentially polymorphically pure form.
Finally, another objective of the present invention is the provision of a crystalline form, preferably a crystalline anhydrous form of avibactam sodium, which is reliably producible on an industrial scale in polymorphically or essentially polymorphically pure and/or stable form.